This R01 application, entitled ?Alzheimer?s dementia onset and progression in international cohorts (Amended)? is a resubmission in response to PAR-17-054. By the year 2050 it is projected that there will be 13.5 million Americans with Alzheimer?s disease (AD) at a cost of $1.1 trillion. The increasing incidence of AD and related dementias presents a massive global health challenge requiring a committed response from researchers, clinicians and funding bodies. The rise in dementia diagnoses presents multiple challenges for researchers and clinicians alike. Paramount amongst these are early, accurate identification of dementia and its aetiology, in parallel with ensuring that clinical research findings are translated into tangible outcomes in the prevention, diagnosis, treatment, and care for people at risk of or manifesting dementia. To facilitate this, a better understanding of the risk and protective factors which precipitate or delay a dementia diagnosis is essential. Our proposal will leverage the power of five leading well characterized Alzheimer?s cohorts to clarify risk and protective factors for Alzheimer?s disease and related dementias: the Adult Children Study (ACS), the Alzheimer?s Disease Neuroimaging Initiative (ADNI), the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), the Dominantly Inherited Alzheimer Network (DIAN) and the National Alzheimer's Coordinating Center (NACC). This international consortium will provide us with access to data spanning the entire disease lifespan; from its preclinical stages through to post mortem analyses. Data from participants presenting at three or more timepoints will be used to ensure robust findings. This application will establish and validate the impact of demographics, genotype and comorbidities on the onset and progression rates of Alzheimer?s dementia. This work will enable us to establish and validate hazard scores for disease onset and severity using clinical markers across the domains of cognition, neuroimaging, and biomarkers. The datasets of these cohorts will be harmonized to enable an improved understanding of the risk and protective factors for Alzheimer?s dementia. This application will lead to the generation of risk hazard scores based on clinically available technologies. These findings will be directly transferable to the clinical setting and will also enable more accurate identification of suitable candidates for clinical trials targeting Alzheimer?s disease.